Tetrahydro β-carbolines having anti-hypertensive activity

ABSTRACT

Disclosed are novel tetrahydro  beta -carbolines of the formula: &lt;IMAGE&gt;   wherein R is H, OCH3 or F; R1 is H or CH3 and R2 is H or COOR3 where R3 is H or CH3. These compounds are useful as antihypertensive agents.

BACKGROUND OF THE INVENTION

U.S. Pat. No. 3,202,666, issued Aug. 24, 1965, discloses substituted9H-pyrido (3,4-b) indole-1-carboxylic acid and derivatives thereofcharacterized by the formula: ##STR2## where R is hydrogen or a loweralkyl group of 1-4 carbon atoms. These compounds are said to havesignificant sedative and antiparasitic activity.

In U.S. Pat. No. 3,202,667, issued Aug. 24, 1965 compounds of theformula: ##STR3## where R is hydrogen or lower alkyl of 1-4 carbon atomsare disclosed as having utility as anti-inflammatory and sedativeagents.

South African Pat. No. 65/5046 dated Sept. 16, 1965, disclosesβ-carboline derivatives of the formula: ##STR4## where R₁ can behydrogen, R₂ can be carboxy or alkoxycarbonyl, R₃ can be hydrogen and R₄and R₅ are hydrogen or alkyl radicals. The compounds disclosed in thispatent are further defined in that the benzene ring A may be substitutedby one or more alkoxy radicals. These compounds are disclosed as havingutility as analgesic agents.

SUMMARY OF THE INVENTION

The present invention involves novel tetrahydro β-carbolines of theformula: ##STR5## In the above formula R is H, OCH₃ or F; R₁ is H or CH₃and R₂ is H, COOH, or COOCH₃. The description of these compounds isfurther limited in that R is F or OCH₃ only when R₂ is H.

These compounds have therapeutic utility as antihypertensive agents.

DESCRIPTION OF THE INVENTION

The compounds of this invention are prepared according to Scheme I whereR is as defined and limited above.

Referring to Scheme I, the indole β-aminoacid 1 is treated at roomtemperature with an equivalent amount of glyoxalic acid dissolved in H₂O (e.g., 35 mmole dissolved in 100 ml of H₂ O). The pH of the solutionis adjusted to pH 4 by adding base )e.g., 10% KOH, 10% K₂ CO₃, etc.).The diacid or monoacid monoester 2 is filtered after stirring at roomtemperature for 24 hours.

Compound 2 is converted to the diester 4 by treating a methanol solutionwith an equivalent amount of thionyl chloride at 0° C. After addition,the mixture is stirred at room temperature overnight. The free base ofthe diester is liberated from the hydrochloride salt using a base (e.g.,6% K₂ CO₃). One equivalent of HCl (4N HCl in dioxane was used; othersolvents are also suitable) is added and the diester hydrochloride isfiltered.

Compound 2 is converted to compound 3 by refluxing in ≈10% HCl for 2hours.

Compound 5 is prepared in a manner similar to the preparation ofcompound 3. ##STR6##

The preparation and pharmacological evaluation of these compounds isfurther illustrated by the following examples:

EXAMPLE 1 1,2,3,4-Tetrahydro-β-Carboline-1,4-Dicarboxylic Acid (TR-8021)

3-Amino-2-(3-indolyl)propanoic acid (6 g; 0.03 mole) was mixed with 55ml of water. Then glyoxalic acid (80% in water) (3 g; 30 mmole)dissolved in 50 ml of water was added and with rapid stirring 10% K₂ CO₃solution was added to pH 4.00. The mixture was stirred for a period of 3days. A white precipitate was collected, washed with 400 ml of water anddried overnight with isopropyl alcohol. Yield 3 g (38%) mp 230°-231° C.

Anal. calcd. for C₁₃ H₁₂ N₂ O₄ : C, 60.05; H, 4.65; N, 10.76. Found: C,60.02; H, 4.71; N, 10.76.

EXAMPLE 2 Dimethyl-1,2,3,4-Tetrahydro-β-Carboline-1,4-DicarboxylateHydrochloride (TR-8022)

1,2,3,4-Tetrahydro-β-carboline-1,4-dicarboxylic acid (2 g; 0.007 mole)prepared in Example 1 was dissolved in 50 ml of methanol. It was cooledin a dry-ice acetone bath at 0° C. Then thionyl chloride (1.38 ml, 0.019mole) was added dropwise. The mixture was stirred at room temperaturefor 24 hours and the solvent removed in vacuo. The residue waspartitioned in ethyl acetate and 6% K₂ CO₃ solution. The organic layerwas dried over MgSO₄, filtered, and treated with 4N-HCl in dioxane to pH5. A white precipitate was collected by filtration, washed with cooledethyl acetate and dried in an oven at 60° C. for 24 hours. Yield 0.7 g(30%) mp 183°-184° C.

Anal. calcd. for C₁₅ H₁₇ ClN₂ O₄ : C, 55.47; H, 5.28; N, 8.63. Found: C,55.11; H, 5.44; N, 8.42.

EXAMPLE 3 1,2,3,4-Tetrahydro-β-Carboline-4-Carboxylic Acid Hydrochloride(TR-8025)

Four (4) g; 0.16 mole of 1,2,3,4-tetrahydro-β-carboline-1,4-dicarboxylicacid (TR-8021) prepared in Example 1 was mixed with 40 ml concentratedHCl and 120 ml of water. The mixture was refluxed at 80° C. (oil-bath)for 2 hours. A white precipitate was collected by filtration, and washedwith small amount of cooled water. The crude material was boiled inwater, filtered through celite and cooled. The precipitate was collectedand dried in the oven at 60° C. Yield: 3 g; (74%). MP 280°-281° C.

Anal. calcd. for C₁₂ H₁₂ N₂ O₂.HCl: C, 57.03; H, 5.19; N, 11.09. Found:C, 56.77; H, 5.36; N, 10.96.

EXAMPLE 4 Methyl 1,2,3,4-Tetrahydro-β-Carboline-4-CarboxylateHydrochloride (TR-8026)

1,2,3,4-Tetrahydro-β-carboline-4-carboxylic acid hydrochloride (3 g,0.012 mole) (TR-8025) prepared in Example 3 was mixed with 50 ml ofmethanol. It was cooled at 0° C. Then thionylchloride (2 ml, 0.028 mole)was added dropwise. The mixture was stirred at room temperature for 24hours. The solvent was removed in vacuo. The residue was partitioned inethyl acetate/6% K₂ CO₃ solution. The organic phase was dried overMgSO₄, filtered and treated with 4 NHCl in dioxane to pH=5. A whitesolid was collected. Yield: 2 g (62%) mp 246°-247° C.

Anal. calcd. for C₁₃ H₁₄ N₂ O₂.HCl: C, 58.49; H, 5.67; N, 10.50. Found:C, 58.52; H, 5.95; N, 10.52.

EXAMPLE 5 Methyl 6-Methoxy-1,2,3,4-Tetrahydro-β-Carboline-4-CarboxylateHydrochloride (TR-3938)

The procedures in Examples 1, 3 and 4 were followed starting with ethyl3-amino-2-[3-(5-methoxyindolyl)]propanoate hydrochloride. Yield, 28%. MP253°-254° C.

Anal. calcd. for C₁₄ H₁₇ ClN₂ O₃ : C, 56.65; H, 5.77; N, 9.44. Found: C,56.20; H, 5.72; N, 9.28.

EXAMPLE 6 6-Fluoro-1,2,3,4-Tetrahydro-β-Carboline-1,4-Dicarboxylic Acid(TR-8000)

TR-8000 was prepared as in Example 1 starting with3-amino-2-(5-fluoro-3-indolyl)propanoic acid. Yield, 22%. MP 233°-234°C.

Anal. Calcd. for C₁₃ H₁₁ FN₂ O₄ : C, 56.16; H, 3.99; N, 10.08. Found: C,55.20; H, 4.10; N, 9.92.

EXAMPLE 7 6-Fluoro-1,2,3,4-Tetrahydro-β-Carboline-4-Carboxylic AcidHydrochloride (TR-8001)

TR-8001 was prepared as in Example 3 starting with TR-8000 (Example 6).Yield, 85%. MP 277°-278° C.

Anal. calcd. for C₁₂ H₁₂ ClFN₂ O₂ : C, 53.24; H, 4.47; N, 10.35. Found:C, 53.13; H, 4.41; N, 10.49.

EXAMPLE 8 Methyl 6-Fluoro-1,2,3,4-Tetrahydro-β-Carboline-4-CarboxylateHydrochloride (TR-8003)

TR-8003 was prepared as in Example 4 starting with TR-8001 (Example 7).Yield, 70%. MP 257°-258° C.

Anal. calcd. for C₁₃ H₁₄ ClFN₂ O₂ : C, 54.84; H, 4.96; N, 9.84. Found:C, 54.85; H, 5.00; N, 9.90.

EXAMPLE 9 Methyl 6-Chloro-1,2,3,4-Tetrahydro-β-Carboline-4-CarboxylateHydrochloride (TR-8161)

The procedures in Examples 1, 3 and 4 were followed starting with3-amino-2-(5-chloro-3-indolyl)propanoic acid. Yield, 21%. MP 252°-254°C.

Anal. calcd. for C₁₃ H₁₄ Cl₂ N₂ O₂ : C, 51.84; H, 4.68; N, 9.30. Found:C, 51.92; H, 4.71; N, 9.03.

EXAMPLE 10 Methyl 6-Methoxy-1,2,3,4-Tetrahydro-β-Carboline-1-CarboxylicAcid-4-Carboxylate (TR-8397)

Methyl 3-amino-2-(5-methoxyindol-3-yl) propionate (11 g; 0.038 mole) wasmixed with 50 ml of water and glyoxylic (80% in water) (4.25 g; 0.038mole) dissolved in 100 ml of water was added and a 10% K₂ CO₃ solutionwas added with rapid stirring to pH 4.0. After four days of stirring theresultant white precipitate was collected, washed with 500 ml of waterand dried overnight over isopropyl alcohol. Yield 10 g (80%). MP223°-224° C.

Anal. calcd. for C₁₅ H₁₆ N₂ O₅ : C, 59.21; H, 5.30; N, 9.21. Found: C,58.74; H, 5.46; N, 9.13.

EXAMPLE 11 Methyl 6-Fluoro-1,2,3,4-Tetrahydro-β-Carboline-1-CarboxylateHydrochloride (TR-8229)

A. 6-fluoro-1,2,3,4-tetrahydro-β-carboline-1-carboxylic acid wasprepared as follows:

Seven (7) g; 0.033 mole of 6-fluorotryptamine hydrochloride was mixedwith 60 ml of water. At this point glyoxylic acid (80% in water) (3.5 g;0.035 mole) dissolved in 50 ml of water was added and, with rapidstirring, 10% K₂ CO₃ solution was added until the pH reached 4.0. Themixture was stirred for a period of 2 days resulting in a whiteprecipitate which was collected, washed with 400 ml of water and driedovernight over 150 ml of propyl alcohol. Yield 4.5 g (58%) MP 237°-238°C.

Anal. calcd. for C₁₂ H₁₁ N₂ O₂ : C, 61.59; H, 4.74; N, 11.97. Found: C,60.80; H, 4.67; N, 11.57.

B. The title compound was prepared by mixing6-fluoro-1,2,3,4-tetrahydro-β-carboline-1-carboxylic acid (2 g; 0.0085mole) with 60 ml of methanol. After cooling at 0° C., thionyl chloride(2 ml., 0.028 mole) was added dropwise and the mixture stirred at roomtemperature for 24 hours whereupon the solvent was removed in vacuo. Theresidue was partitioned in ethylacetate/6% K₂ CO₃ solution whereupon theorganic phase was dried over MgSO₄, filtered and treated with 4 N HCl indioxane to pH 5. A white solid product was collected. Yield: 1.2 g (38%)MP 219°-220° C.

Anal. calcd. for C₁₃ H₁₈ FN₂ O₂ HCl: C, 54.85; H, 5.00; N, 9.90. Found:C, 55.22; H, 4.97; N, 9.73.

Determination of Anti-Hypertensive Activity Experiments in Rats

The acute antihypertensive activity of test compounds was determined inrats made hypertensive by the procedure of A. Grollman, Proc. Soc.Exper. Biol. Med. 57:102 (1944) by applying a figure of eight (8)ligature to one (1) kidney and removing the contralateral kidney twoweeks later. At least four weeks after the second operation, the ratswere subjected to indirect systolic blood pressure measurements with anoccluding cuff and pulse sensor applied to the tail. Measurements weremade before and at 1, 2, 4, 6 and 8 hours after the oral administrationof the test compounds at a dose of 10 mg/kg. Each compound was testedinitially in five (5) rats and if it elicited a significant decrease inpressure at any of the observation periods, it was tested in anotherfive (5) animals and results of the two (2) experiments were averaged.Statistical significance of differences between initial and posttreatment values was determined by Wilcoxon's signed rank test (F.Wilcoxon and R. A. Wilcox, Some Rapid Approximate StatisticalProcedures, Lederly Laboratories, Pearl River, 1964).

The results of these experiments are set out in Table I.

                                      TABLE I                                     __________________________________________________________________________     ##STR7##                                                                     Compound                                                                            R   R.sub.1                                                                          R.sub.2                                                                             n.sup.1                                                                          C.sup.2                                                                          1 hr.                                                                            2 hr.                                                                            4 hr.                                                                            6 hr.                                                                            8 hr.                                                                            2-8 hr.                               __________________________________________________________________________    TR-3938                                                                             OCH.sub.3                                                                         CH.sub.3                                                                         H     10 187                                                                               0 -6 -9*                                                                              +1 +4 -2                                    TR-8000                                                                             F   H  COOH  5  193                                                                              -4 +1 -1  0 +4 +1                                    TR-8001                                                                             F   H  H     10 206                                                                              -4 -2 -8*                                                                              -3  0 -3                                    TR-8003                                                                             F   CH.sub.3                                                                         H     10 195                                                                              -18*                                                                             -20*                                                                             -10                                                                              -4 +2 -8                                    TR-8021                                                                             H   H  COOH  10 192                                                                              -14*                                                                             -18*                                                                             -16*                                                                             +8 +17*                                                                             -3                                    TR-8022                                                                             H   CH.sub.3                                                                         COOCH.sub.3                                                                         10 191                                                                              -9*                                                                              -10                                                                              -18*                                                                             -11*                                                                             -8 -10                                   TR-8025                                                                             H   H  H     5  188                                                                              -10                                                                              -6 +5 -4 -3 -2                                    TR-8026                                                                             H   CH.sub.3                                                                         H     5  176                                                                              -8 -7 -2 +5 +1 -1                                    TR-8161                                                                             Cl  CH.sub.3                                                                         H     5  182                                                                              -3 +8 +5 +7 +5 +6                                    TR-8397                                                                             OCH.sub.3                                                                         CH.sub.3                                                                         COOH  5  188                                                                              -1 +1 +1 +3 +12                                      TR-8229                                                                             F   ** COOCH.sub.3                                                                         5  184                                                                              +4 +1 -4 +1 +7                                       __________________________________________________________________________     .sup.1 n = number of test animals                                             .sup.2 C = initial value                                                      * = statistically significant                                                 ** = no substitution at 4position-                                       

The compounds of this invention possess unexpected pharmacologicalproperties that render them useful as therapeutic agents for thetreatment of hypertension in an individual for whom such therapy isindicated. The term individual is intended to mean a human being or anexperimental animal that is used as a model for a human being. Theeffective dosage may vary from individual to individual but is easilydetermined by one skilled in the art without undue experimentation. Doseforms for the administration of the compounds of this invention may beprepared by recognized methods in the pharmaceutical sciences.Particular dose forms can be administered by conventional known methodsof therapeutic administration such as oral, intravenous, parenteral orthe like.

What is claimed is:
 1. Tetrahydro β-carbolines of the formula: ##STR8##wherein R is H, OCH₃ or F, R₁ is H or CH₃ and R₂ is COOH or COOCH₃.
 2. Acompound as described in claim 1 wherein R is H, R₁ is H and R₂ is COOH.3. A compound as described in claim 1 wherein R is H, R₁ is CH₃ and R₂is COOCH₃.
 4. A compound as described in claim 1 in the form of itspharmaceutically acceptable organic or inorganic acid addition salt. 5.A method of treating hypertension in an individual for whom such therapyis indicated which method comprises administering orally or parenterallyto such individual an antihypertensively effective amount of a compoundcharacterized by the formula: ##STR9## wherein R is H, OCH₃ or F; R₁ isH or CH₃ and R₂ is COOH or COOCH₃.
 6. The method of claim 5 wherein thecompound administered is further defined in that R is H, R₁ is H and R₂is COOH.
 7. The method of claim 5 wherein the compound administered isfurther defined in that R is H, R₁ is CH₃ and R₂ is COOCH₃.
 8. Themethod of claim 5 wherein the compound administered is in the form ofits pharmaceutically acceptable organic or inorganic acid addition salt.